With this analytic epidemiologic study, we begin investigating situations in which the treatment of one condition may exacerbate other conditions or adversely affect other health outcomes. Despite potential harms to the large number of older individuals with multiple co-occurring health conditions, this topic has received little research attention. We explore the capability of using large national population-based cohorts and novel analytical techniques to compare the benefits and harms of different intervention strategies, across a range of health outcome domains, in complex older adults with multi-morbidity. To develop our strategy, we begin by investigating Beta-Blocker (2-Blocker) intensity in persons with co-occurring coronary artery disease (CAD) and chronic obstructive pulmonary disease (COPD). Once we have tested the method with this important clinical question, we will extent to other sets of conditions and medications. This project builds on our ongoing research on multi-morbidity that includes mapping disease-specific outcomes onto universal health outcomes, determining tradeoffs among competing conditions, and ascertaining the contribution of multiple co-occurring conditions to death and other health outcomes. Our methodological aim is to develop an innovative method for comparing different treatment strategies in situations in which the treatment of one condition could exacerbate other conditions or affect other health outcomes. Using our novel methods, we will test the hypothesis that, among comparable older adults with co- occurring CAD and COPD, greater 2-Blocker intensity is associated with fewer CV events and lower mortality but more frequent adverse pulmonary outcomes;worse dyspnea, fatigue, and activity levels and greater disability than no or lower 2-Blocker intensity. In secondary analyses, we will explore these aims in relevant subgroups defined by age, CAD and COPD severity, gender, race, and co-morbidity burden. Two national, population-based cohorts, the Medicare Current Beneficiary Survey and the Medical Expenditure Panel Survey will be studied (study sample 35,000-40,000). Both have a wealth of longitudinal participant-reported, medication, and claims/health care utilization data. This depth and breadth of data allows us to use innovative analytical techniques to assess the effects of treatments on disease-specific and universal health outcomes (e.g. disability, symptoms burden, functional limitations, and death), accounting for propensity to receive the treatment, and other confounders. We propose a new paradigm for quantifying the harms and benefits of treatments in complex older persons with multiple conditions. Our ultimate goal is to develop a method for determining the optimal treatments for older adults with multiple conditions that maximizes benefits and minimizes harms within the outcome domain(s) of highest priority for each patient. PUBLIC HEALTH RELEVANCE: Among persons with multiple chronic diseases, treatments for one disease may exacerbate co-occurring diseases or adversely affect overall health outcomes. We are exploring whether Beta-Blocker use in older adults with co-occurring coronary artery disease (CAD) and chronic obstructive pulmonary disease benefits cardiac outcomes but worsen pulmonary outcomes, symptoms, or activity levels. Study results can help determine the net benefit or harm of commonly recommended treatments among the growing number of older adults with multiple health conditions.